Dihydrolipoamide dehydrogenase deficiency (dihydrolipoamide dehydrogenase deficiency) - Gen DLD.

Dihydrolipoamide dehydrogenase deficiency is a serious disease that can affect various body systems. Usually associated signs and symptoms appear shortly after birth and can vary widely among affected individuals.

A common feature of dihydrolipoamide dehydrogenase deficiency is lactic acidosis, which can be life threatening and can cause nausea, vomiting, severe breathing problems and an abnormal heart rhythm. Neurological problems are also common in affected individuals. Early symptoms in affected children usually hypotonia and lethargy. As the problems get worse, affected children may have difficulty eating, decreased alertness and seizures. Also, this disease can lead to liver problems such as hepatomegaly and hepatic failure , which can be life threatening. In some affected individuals, liver disease can begin at any time, from infancy to adulthood. Liver problems are usually associated with recurrent vomiting and abdominal pain. In addition, in rare cases, people with dihydrolipoamide dehydrogenase deficiency have skeletal muscle weakness, drooping eyelids and cardiomyopathy. Associated features include hyperammonemia, ketoacidosis or hypoglycemia.

Usually the signs and symptoms of dihydrolipoamide dehydrogenase deficiency occurs in episodes that can be caused by fever, injury or other stressors in the body. Many affected infants do not survive the first years of life because of the severity of these episodes. Often the affected individuals survive beyond early childhood have delayed growth and neurological problems, including mental retardation, spasticity, ataxia and seizures.

This process is due to mutations in the gene DLD, located on the long arm of chromosome 7 (7q31-q32). This gene encodes the enzyme dihydrolipoamide dehydrogenase. This enzyme is a subunit, designated E3 component, various enzyme complexes that act together. These complexes are essential for the decomposition of certain molecules to produce energy in cells. One of the enzyme complexes that include dihydrolipoamide dehydrogenase is BCKD. The BCKD enzyme complex takes a step in the decomposition of three amino acids obtained from dietary leucine, isoleucine and valine. The breakdown of these aminoacids produces molecules that can be used for energy. Dihydrolipoamide dehydrogenase is also part of the pyruvate dehydrogenase complex (PDH). This enzyme complex plays an important role in the production of energy for cells, converting pyruvate, which is formed by the decomposition of carbohydrates, another molecule called acetyl-CoA. The conversion of pyruvate is essential to start the series of chemical reactions that ultimately produces adenosine triphosphate in (ATP), the major source of cellular energy. Likewise, dihydrolipoamide dehydrogenase is part of a third enzyme complex involved in cellular energy production. This complex, called oxoglutarate dehydrogenase complex (?KGDH), convert ?-ketoglutarate to succinyl-CoA.

They have identified at least 17 mutations in the DLD gene causing dihydrolipoamide dehydrogenase deficiency. Most DLD mutations change individual amino acids in dihydrolipoamide dehydrogenase, which prevents BCKD, PDH and ?KGDH complex function properly. BCKD deterioration of function leads to an accumulation of valine, isoleucine, leucine and its byproducts in the body. This accumulation is toxic to cells and tissues, especially in the nervous system and contributes to neurological problems in people with dihydrolipoamide dehydrogenase deficiency. A reduction in the role of pyruvate dehydrogenase resulting in an accumulation of pyruvate is converted to lactic acid, which contributes to lactic acidosis in affected individuals. For its part, the deterioration of ?KGDH leads to the accumulation of alpha-ketoglutarate and probably also contributes to lactic acidosis. The reduced function of these three enzyme complexes also reduces cellular energy production. The brain, which requires large amounts of energy in particular, is severely affected, leading to neurological problems associated with dihydrolipoamide dehydrogenase deficiency. Liver problems are probably related to decreased energy production in cells. The degree of deterioration of each complex contributes to the variability in the characteristics of this disease.

This disease is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.  

Tests in IVAMI: in IVAMI perform detection of mutations associated with dihydrolipoamide dehydrogenase deficiency, by complete PCR amplification of the exons of the gene DLD, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).